Multifactorial Inheritance

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Multifactorial Inheritance
Prasit Chanarat, M.S. (Clin.Path.)
Department of Clinical Microscopy Faculty of
Associated Medical Sciences Chiang Mai University
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Objectives

• define the terms polygenic, multifactorial, and
  heritability
• explain the difference between continuous
  variation and discontinuous variation
  including threshold traits and common diseases
  
• discuss the benefits and limitations of empiric
  risk counselling
• explain the characteristics of multifactorial
  inheritance and apply these to estimation of
  recurrence risk
• give examples of conditions that are inherited
  in a multifactorial manner
• discuss the use of folic acid (folate) for the
  prevention of neural tube defects

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Definitions
Multifactorial inheritance - traits determined
by a combination of multiple genetic and
non-genetic (environmental) factors Polygenic -
traits determined by the combined additive
effect of 2 or more genes Heritability - the
proportion of a trait that is genetically
determined or an estimation of the genetic
contribution to a multifactorial condition
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Clinical Cases
Bua-Kum goes into labor after an uneventful
pregnancy, she had declined options for prenatal
diagnosis as soon as the baby is delivered. She
is noted to be abnormal the legs are flaccid,
and there is a large mass protruding from her
back in the lumbar area
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Neural tube defect
closure of the neural tube may occur at
multiple levels anterior neuropore - 25 days
post-conception posterior neuropore- 27 days
post-conception failure of closure neural tube
defect caudal portion - solid core of tissue
becomes canalized due to cell death at the
centre, so a tube is formed
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• TYPES OF NEURAL TUBE DEFECT
• entire neural tube open -craniorachischisis
• most anterior part - anencephaly
• hindbrain - encephalocele
• different levels of the spine - most common
• is the lumbar region
• meningocele - meninges (covering of the nervous
  system)
• myelomeningocele - meninges and part of the
  spinal cord
• spina bifida occulta - incomplete bony fusion of
  an arch
• of the vertebrae , can be associated with
  sacral dimple,
• change in skin pigmentation or a tuft of hair

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Anencephaly
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Implication of the Diagnosis
Risk of infection - antibiotics and prompt
closure if possible Myelomeningocele -
paralysis of muscles innervated from spinal
nerves originating below the level of the
defect - variable depending on nerve
involvement and level of the defect -
physical therapy etc. Disruption of nerve
innervation bladder and bowel - urinary
retention and constipation associated CNS
abnormalities - Arnold Chiari malformation,
hydrocephalus
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Recurrent risk for NTD
Require a detailed family history (3
generation minimum) Risks apply to all types of
NTD but about 2/3 of the risk is for the same
type of defect Empirical data is used to
calculate the recurrence risk (based on the
observation that some disorders tend to
cluster in families)
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Recurrent risk for Neural tube Defects
Affected Relatives Recurrence Risk ()
1st degree (parent, sibling) 3.2
2nd degree (niece, nephew, 0.5
aunt, uncle)
3rd degree (cousin, great aunt, 0.17
great uncle)
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Characteristics of Multifactorial Inheritance

• Phenotype is familial but no characteristic
• pattern of inheritance
• for first degree relatives the risk for being
• affected is about the square root of the
• population risk
• when more than one relative is affected the
• recurrence risk is higher

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Characteristics of Multifactorial Inheritance

• for some conditions - the more severe the
• phenotype the higher the recurrence risk
• when the phenotype is more common in one
• sex, the risk is higher for relative of the
• proband of the less susceptible sex
• higher risk if the parents are consanguineous

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• Using empirical risk data for genetic
  counselling
• are specific to the condition
• must consider the possibility of an underlying
• syndrome (including a single gene disorder or
• chromosome abnormality)
• recurrence risks represent averages - the
• actual risk in a given family may be higher
• or lower
• can vary from one population to another for
• one condition
• recurrence risk increases with the proximity
• of the relationship with the proband and with
• number of affected individuals in the family
• can vary between sexes

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MULTIFACTORIAL INHERITANCE

• explanation could be that multiple genes exert
• an additive effect - polygenic therefore
• doesnt account for environmental factors
• example - height

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One locus - 3 Alleles
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Two loci - 3 Alleles
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HYPOTHETICAL MODEL FOR HEIGHT

• add the environmental effect of poor nutrition
• --gt height will decrease
• therefore - multiple genes and environmental
• influences contribute to multifactorial traits
• twin studies help to define to what degree a
• trait is genetic

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Multifactorial Inheritance - Continuous Variation

• - a variety of traits known as quantitative
  traits
• - frequently follow a normal distribution
• - i.e. height, weight, intelligence
• - abnormality is considered an extreme variant
• of the normal distribution

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Multifactorial Inheritance - Discontinuous
Variation

• Common diseases
  Threshold traits -
• - appear to be multifactorial -
  do not follow a normal
• - many common in the adult popn
  distribution
• - i.e. rheumatoid arthritis, epilepsy, -
  either present or absent
• hypertension, diabetes, multiple -
  sharp delineation between
• sclerosis, coronary artery disease
  normal and abnormal
• phenotypes
• - threshold model

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Empirical daia on recurrence risk of selected
congenital anomalies
Anomaly Popn incidence RR in 1st
relative
Cleft lip 1/1000 4.9 cleft
palate
Cong. Dislocation 1/1000 3.5 of hip
Pyloric stenosis 1/500 3.2
Club foot 1/500 2.8
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Trait Concordance
Concordance Identical twins ()
Full sibling ()
Cleft lippalate 40 5
Pyrolic stenosis 22 4
Club foot 32 3
Cong. Dislocation 33 4
of hip
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Genetic variance Genetic
variance Environmental variance
H
CMZ - CDZ 100 -
CDZ
H
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Heritability
Offspring - parent H 2b
Offspring - mid-parent H b
Sib - sib H 2r
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Threshold model
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THRESHOLD MODEL
risk may differ depending on sex

• - pyloric stenosis
• - more common in males
• - a couple with an affected daughter has a higher
  
• recurrence risk compared with a couple with an
  
• affected son
• - recurrence would still be more likely to occur
  
• in a son than in a daughter

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Example - Threshold higher for a female
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CASE - genetic counselling

• recurrence risk - 3 empirically
• prevention - 4mg folate from 1 month before
• conception until 2 months after conception
• (estimated that half of neural tube defects
• worldwide could be prevented is all women
• took periconceptual folate)
• prenatal diagnosis options
• - maternal serum AFP
• - amniotic fluid AFP
• - 19 week ultrasound

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The End